Wnt signaling is one of the key oncogenic pathways in multiple cancers1,2. Upon binding to its receptors, low density lipoprotein receptor-related protein 5/6 (LRP5/6) and Frizzled (FZD) (both are single pass transmembrane receptors required for Wnt signalling) at the plasma membrane, Wnt ligand triggers the disruption of β-catenin degradation machinery composing of Axin2, GSK3β, APC and other proteins, which leads to the accumulation of β-catenin in the cytoplasm3. Elevated levels of β-catenin ultimately leads to its translocation into the nucleus to form a complex with LEF/TCF, and drive downstream gene expression3.
Dysregulation of Wnt signaling1 can occur through mutations of downstream components such as APC and β-catenin that are well documented in colon cancer1. In addition, overexpression of Wnt ligands or co-stimulants, such as RSPO2/3, or silencing of Wnt inhibitor genes have been reported in various cancers1,4. Furthermore, mutations of pan-Wnt pathway components, such as Axin1/2 or RSPO co-receptors RNF43/ZNFR3, play a potential key role in pancreatic, colon, and hepatocellular carcinoma4-6. Both unbiased and targeted mutations of the Wnt pathway in animal models have demonstrated the oncogenic signaling function of this pathway7,8. In addition to the canonical Wnt pathway, there is emerging evidence that non-canonical Wnt signaling, through FZD and VANGL, is critical for various aspects of tumorigenesis including cell migration and tumor metastasis9.
Both canonical and non-canonical Wnt signaling activities are dependent on the Wnt ligand. During the biosynthesis of Wnt ligands, Wnt undergoes post-translational acylation that is mediated by Porcupine (PORCN), a membrane bound O-acyltransferase3,10. PORCN is specific and dedicated to Wnt post-translational acylation, which is required for subsequent Wnt secretion11. Loss of PORCN leads to inhibition of the Wnt ligand driven signaling activities in knockout mouse models12,13. In humans, loss of function (LoF) mutation of the PORCN gene causes focal dermal hypoplasia in an X-linked dominant disorder associated with a variety of congenital abnormalities in both heterozygotes and those with mosaicism for the PORCN gene. This phenotype is consistent with the role of Wnt signaling pathway during embryogenesis and development14,15.
Success so far in therapeutically targeting the Wnt signalling has been limited. This is largely due to the lack of effective therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. As a result to differences in a complex cascade of regulatory mechanisms in the cell cycle and differential gene expression different cancer types may respond differently to the same active compound. Knowledge on specific biomarkers which indicate the sensitivity of cells to the therapy with a PORCN inhibitor or Wnt inhibitor is also scarce.